Maribavir isomers, compositions, methods of making and methods of using

ABSTRACT

The invention relates to novel compositions and methods of using maribavir which enhance its effectiveness in medical therapy, as well as to maribavir isomers and methods of use thereof for counteracting the potentially adverse effects of maribavir isomerization in vivo in the event it occurs.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication No. 61/407,637, filed Oct. 28, 2010, the entire disclosureof which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

The present invention relates to compositions and methods for enhancingthe therapeutic efficacy of the compound5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(also known as 1263W94 and maribavir), as well as to maribavir isomersand a method of making such isomers.

5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoleis a benzimidazole derivative useful in medical therapy. U.S. Pat. No.6,077,832 discloses5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoleand its use for the treatment or prophylaxis of viral infections such asthose caused by herpes viruses. The compound as disclosed in U.S. Pat.No. 6,077,832 is an amorphous, non-crystalline material.

The structure of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoleis:

The preparation of certain unique crystalline forms and solvate forms ofmaribavir, as well as pharmaceutical formulations thereof and their usein therapy are described in U.S. Pat. Nos. 6,469,160 and 6,482,939.

The present invention has arisen out of the unexpected discovery thatmaribavir may isomerize under in vivo conditions to one or moreconfigurational stereoisomers or constitutional isomers. The maribavircompound contains 4 (four) chiral carbon centers in the ribofuranosylmoiety and therefore maribavir is just one of 16 (sixteen) potentialstereoisomers that may be formed under various in vivo conditions.

Under in vivo conditions, maribavir can isomerize to other compoundsthat may (or may not) have the same or similar chemical, physical andbiological properties. The in vivo isomerization of maribavir results inconversion of maribavir to other isomers that have the same molecularformula but a different molecular structure. The different molecularstructures can be grouped into isomers that have different connectivityof the constituent atoms (constitutional isomers) or grouped intoisomers that have the same “connectivity” but differ in the way theatoms and groups of atoms are oriented in space (configurationalstereoisomers). Such molecular conversion in vivo is believed to resultin the dilution of the effective maribavir concentration in the hostthat was treated with maribavir. The in vivo isomerization transformsand distributes dosed maribavir material into other molecular entitiesthat do not necessarily have the same or similar biological activity. Ifthe isomerization results in the formation of isomers that have a lowerdegree of corresponding biological activity relative to the activity ofmaribavir, then the isomerization will decrease the effective biologicalactivity of maribavir dose administered to a host.

A recent maribavir Phase 3 clinical trial conducted by ViroPharmaIncorporated (the 300 Study) that evaluated maribavir forcytomegalovirus (CMV) prophylaxis in allogeneic stem cell, or bonemarrow, transplant (SCT) patients did not achieve its primary endpoint.In the primary analysis, there was no statistically significantdifference between maribavir and placebo in reducing the rate of CMVdisease. In addition, the study failed to meet its key secondaryendpoints (ViroPharma Press Release dated Feb. 9, 2009). The 300 Studyresult appeared at first blush to be inconsistent with an earlierproof-of-concept (POC) maribavir Phase 2 clinical trial (the 200 Study)wherein ViroPharma reported positive preliminary results that showedthat maribavir inhibited CMV reactivation in SCT patients. The data fromthis study demonstrate that prophylaxis with maribavir displays strongantiviral activity, as measured by significant reduction in the rate ofreactivation of CMV in recipients of allogeneic stem cell (bone marrow)transplants, and that administration of maribavir for up to 12 weeks hasa favorable tolerability profile in this very sick patient population(ViroPharma Press Release date Mar. 29, 2006).

However, the 300 Study result can be explained in terms of the instantmaribavir isomerization theory/discovery. An unrecognized key differencebetween the 200 Study and the 300 Study was that the former provided fora fasted dosing protocol of maribavir, whereas the latter allowed thedosing protocol to be either under fasted or fed conditions (at thediscretion of the clinician). The nature of the patient population inthe 300 Study suggests that probably very few patients were dosed underthe strict fasted dosing protocol that was previously used in the 200Study. The change in dosing protocol in the 300 Study changed not onlythe in vivo dosing conditions for maribavir, but also the nature and/ordegree of isomerization of maribavir that occurs in vivo, so that moremaribavir was isomerized to other less effective compounds, therebyreducing the effective bioavailable concentration of maribavir drugbelow levels necessary to adequately prevent CMV infection and/or CMVre-activation in the host.

The degree and nature of the isomerization of maribavir depends on theparticular in vivo conditions to which the drug is exposed, which arevariable. The potential mechanisms for isomerizing maribavir in vivo areby chemical isomerization (acid, base and/or metal catalyzedisomerization), microbially-mediated isomerization, and/or hostmetabolism induced isomerization. See, for example, Okano, Kazuya,Tetrahedron, 65: 1937-1949 (2009); Kelly, James A. et al., J. Med.Chem., 29: 2351-2358 (1986); and Ahmed, Zakaria et al., Bangladesh J.Sci. Ind. Res., 25(1-4): 90-104 (2000).

Thus, maribavir should be formulated, administered, packaged andpromoted in ways that will prevent or at least reduce the unwantedoccurrence of maribavir isomerization in vivo, thereby enhancing thedrug's bioavailability and efficacy, and/or counteract the potentialadverse effect(s) of maribavir isomerization in vivo, if it occurs.

SUMMARY OF THE INVENTION

The invention generally relates to the unexpected discovery thatmaribavir may isomerize under in vivo conditions to one or moreconfigurational stereoisomers and/or constitutional isomers. Aspect ofthe invention is illustrated below.

The practical applications of the instant discovery and relatedinventions are as follows:

-   -   (1) The invention includes methods of making maribavir isomers        under in vivo conditions (method of administering maribavir as a        prodrug to make other maribavir isomers).    -   (2) The invention includes methods dosing maribavir so as to        mitigate the impact of in vivo maribavir isomerization (such as        dosing under fasted conditions, or increasing the dose of        maribavir).    -   (3) The invention includes maribavir formulations that        effectively mitigate the adverse effects of in vivo maribavir        isomerization (quick release formulations, delayed/controlled        release formulations, combination with antacids,        intravenous (IV) formulations, combination formulations with        antibiotics to prevent microbial isomerization).    -   (4) The invention includes methods of using one or more        maribavir isomers to prevent or treat disease in host (as        antivirals, for example for treating/preventing CMV, EBV, HCV).    -   (5) The invention includes methods of using one or more        maribavir isomers as reference standards in analytical methods        for monitoring the blood plasma concentrations of maribavir and        related isomers.    -   (6) The invention includes methods of monitoring maribavir and        maribavir isomers, and using the information to adjust treatment        protocols (increase/decrease dose, change dosing regimen        fed/fasted, discontinue maribavir therapy, start other therapy).        The analytical methods for monitoring in vivo maribavir        concentrations must be able discriminate between maribavir and        maribavir isomers (for example chiral chromatography, and in        particular LC-MS-MS using a chiral sorbent material in the LC        column).    -   (7) The invention includes a method of more safely and        effectively using maribavir to treat or prevent disease in        humans by including information and guidance in the product        label and/or promotional materials to inform the public as to        how to use the maribavir product so as to avoid or to mitigate        the adverse impact of in vivo maribavir isomerization, and thus        optimize therapeutic efficacy and safety.    -   (8) The invention includes the corresponding inventions related        to the maribavir isomers that are pyranosyl constitutional        isomers of maribavir.

The present invention also relates to a package or kit comprisingtherapeutically effective dosage forms of maribavir, prescribinginformation and a container for the dosage form. The prescribinginformation includes advice to a patient receiving maribavir therapyregarding the administration of maribavir without food to improvebioavailability.

DETAILED DESCRIPTION OF THE INVENTION

The following table contains list of useful dosing protocols that may beused to improve the efficacy and safety for treating a patient withmaribavir.

Fasting Maribavir conditions Route of admin- dosing Dosing (before/afteristration and Protocol amount dosing) dosage form. 01 3200 mg/ NoneOral - tablet - 2 x day immediate release 02 3200 mg/ None IV 2 x day 031600 mg/ None Oral - tablet - 2 x day w/antacids 04 1600 mg/ None Oral-tablet - 1 x day w/antibiotics 05 800 mg/ None Oral- tablet - 3 x daydelayed release 06 800 mg/ None Oral- tablet - 2 x day immediate release07 800 mg/ None IV 1 x day 08 400 mg/ None Oral - tablet - 4 x dayw/antacids 09 400 mg/ None Oral- tablet - 3 x day w/antibiotics 10 400mg/ None Oral- tablet - 2 x day delayed release 11 400 mg/ None Oral -tablet - 1 x day immediate release 12 3200 mg/ 12 hrs/ IV 2 x day 3 hrs13 3200 mg/ 12 hrs/ Oral - tablet - 2 x day 3 hrs w/antacids 14 1600 mg/12 hrs/ Oral- tablet - 2 x day 3 hrs w/antibiotics 15 1600 mg/ 12 hrs/Oral- tablet - 1 x day 3 hrs delayed release 16 800 mg/ 12 hrs/ Oral-tablet - 3 x day 3 hrs immediate release 17 800 mg/ 12 hrs/ IV 2 x day 3hrs 18 800 mg/ 12 hrs/ Oral - tablet - 1 x day 3 hrs w/antacids 19 400mg/ 12 hrs/ Oral- tablet - 4 x day 3 hrs w/antibiotics 20 400 mg/ 12hrs/ Oral- tablet - 3 x day 3 hrs delayed release 21 400 mg/ 12 hrs/Oral - tablet - 2 x day 3 hrs immediate release 22 400 mg/ 12 hrs/ Oral-tablet - 1 x day 3 hrs immediate release 23 3200 mg/ 6 hrs/ Oral -tablet - 2 x day 2 hrs immediate release 24 3200 mg/ 6 hrs/ IV 2 x day 2hrs 25 1600 mg/ 6 hrs/ Oral - tablet - 2 x day 2 hrs w/antacids 26 1600mg/ 6 hrs/ Oral- tablet - 1 x day 2 hrs w/antibiotics 27 800 mg/ 6 hrs/Oral- tablet - 3 x day 2 hrs delayed release 28 800 mg/ 6 hrs/ Oral-tablet - 2 x day 2 hrs immediate release 29 800 mg/ 6 hrs/ IV 1 x day 2hrs 30 400 mg/ 6 hrs/ Oral - tablet - 4 x day 2 hrs w/antacids 31 400mg/ 6 hrs/ Oral- tablet - 3 x day 2 hrs w/antibiotics 32 400 mg/ 6 hrs/Oral- tablet - 2 x day 2 hrs delayed release 33 400 mg/ 6 hrs/ Oral -tablet - 1 x day 2 hrs immediate release 34 3200 mg/ 3 hrs/ IV 2 x day 1hr 35 3200 mg/ 3 hrs/ Oral - tablet - 2 x day 1 hr w/antacids 36 1600mg/ 3 hrs/ Oral- tablet - 2 x day 1 hr w/antibiotics 37 1600 mg/ 3 hrs/Oral- tablet - 1 x day 1 hr delayed release 38 800 mg/ 3 hrs/ Oral-tablet - 3 x day 1 hr immediate release 39 800 mg/ 3 hrs/ IV 2 x day 1hr 40 800 mg/ 3 hrs/ Oral - tablet - 1 x day 1 hr w/antacids 41 400 mg/3 hrs/ Oral- tablet - 4 x day 1 hr w/antibiotics 42 400 mg/ 3 hrs/ Oral-tablet - 3 x day 1 hr delayed release 43 400 mg/ 3 hrs/ Oral - tablet -2 x day 1 hr immediate release 44 400 mg/ 3 hrs/ Oral- tablet - 1 x day1 hr immediate release

In carrying out the method of the invention, it is preferably todetermine the presence and/or concentration of maribavir isomers,especially isomers of diminished therapeutic efficacy in patient bloodplasma samples as part of the method.

As used herein, the terms “fasted conditions”, “fasting conditions” and“without food” are defined to mean, in general, the condition of nothaving consumed food during the period between from at least about 3 to12 hours prior to the administration of maribavir to at least about 1 to3 hours after the administration of maribavir. Other narrower “fastedconditions” are also contemplated herein and described below.

The term “with food” is defined to mean, in general, the condition ofhaving consumed food prior to, during and/or after the administration ofmaribavir that is consistent with the relevant intended definition of“fasted conditions” (which may be narrow or broad depending on thecircumstances). Preferably, the food is a solid food sufficient bulk andfat content that it is not rapidly dissolved and absorbed in thestomach. More preferably, the food is a meal, such as breakfast, lunchor dinner.

The term “isomers” means compounds that have the same molecular formulabut a different molecular structure.

The term “constitutional isomers” is defined to mean isomers that havethe same molecular formula but a different molecular structure whereinthe molecular structures of the isomers have different connectivity ofthe constituent atoms.

The term “configurational stereoisomers” is defined to mean isomers thathave the same “connectivity” but differ in the molecular structure inthe way the atoms and groups of atoms are oriented in space.

The term “immediate release” is defined to mean release of drug fromdrug formulation by dissolution is less than 60 minutes or is otherwiserelease from the drug formulation in less than 60 minutes.

The term “IV” is defined to mean intravenous.

The chemical structure of maribavir and some maribavir isomers are shownbelow. The instant invention contemplates novel formulations, dosagelevels and methods of use of maribavir, the maribavir isomers MFI-01 toMFI-015 (configurational stereoisomers), as well as the maribavirisomers MPI-01 to MPI-016 (constitutional isomers). The invention alsocontemplates the corresponding acyclic constitutional isomers whereinthe sugar moiety is an open chain and attached to the benzimidazole.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows chemical structures of maribavir and maribavirconfigurational stereoisomers that have the same configuration at thefuranosyl anomer carbon.

FIG. 2 shows chemical structures of maribavir configurationalstereoisomers that have the opposite configuration at the furanosylanomer carbon.

FIG. 3 shows chemical structures of maribavir “pyranosyl” constitutionalisomers)

A number of patent and non-patent documents are cited in the foregoingspecification in order to describe the state of the art to which thisinvention pertains. The entire disclosure of each of these citations isincorporated by reference herein.

While certain of the preferred embodiments of the present invention havebeen described and specifically exemplified above, it is not intendedthat the invention be limited to such embodiments. Various modificationsmay be made thereto without departing from the scope and spirit of thepresent invention, as set forth in the following claims. Furthermore,the transitional terms “comprising”, “consisting essentially of” and“consisting of” define the scope of the appended claims, in original andamended form, with respect to what unrecited additional claim elementsor steps, if any, are excluded from the scope of the claims. The term“comprising” is intended to be inclusive or open-ended and does notexclude additional, =recited elements, methods step or materials. Thephrase “consisting of” excludes any element, step or material other thanthose specified in the claim, and, in the latter instance, impuritiesordinarily associated with the specified materials. The phrase“consisting essentially of” limits the scope of a claim to the specifiedelements, steps or materials and those that do not materially affect thebasic and novel characteristic(s) of the claimed invention. Allcompositions or formulations identified herein can, in alternateembodiments, be more specifically defined by any of the transitionalphases “comprising”, “consisting essentially of” and “consisting of”.

What is claimed is:
 1. A method for treatment or prophylaxis of a herpesviral infection in a patient in need thereof comprising administering tosaid patient the compound5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole,or an isomer of said compound, in an amount effective to counteractmolecular conversion of said compound occurring in vivo, and therebyproviding an anti-virally effective amount of said compound to saidpatient.
 2. A method according to claim 1, wherein said amount isgreater than 200 mg per day.
 3. A method according to claim 2, whereinthe amount administered is up to 6400 mg per day.
 4. A method accordingto claim 1, wherein said herpes viral infection is cytomegalovirus.
 5. Amethod according to claim 4, wherein said patient is a stem celltransplant recipient, a liver transplant recipient, or kidney transplantrecipient.
 6. A method according to claim 1, wherein said compound isadministered to said patient under fasted conditions.
 7. The method ofclaim 1 wherein said compound is administered as a compositioncomprising a therapeutically acceptable adjuvant, excipient or carriermedium.
 8. The method of claim 7 wherein said composition is animmediate release formulation, a delayed release formulation, acontrolled release formulation or an intravenous formulation.
 9. Themethod of claim 1, wherein said compound is administered in combinationwith at least one of an antacid which is effective for neutralizing acidthat catalyzes isomerization of maribavir, an antibiotic having activityagainst a microorganism that mediates isomerization of maribavir and anantagonist that inhibits metabolism that induces isomerization ofmaribavir, said isomerization producing a decrease in the therapeuticefficacy of said compound.
 10. A method for the treatment or prophylaxisof herpes viral infection in a patient in need thereof comprisingadministering to said patient one or more maribavir isomers.
 11. Themethod according to claim 10, wherein the prodrug of the maribavirisomers is administered to said patient.
 12. The method according toclaim 11, wherein the prodrug is isomerized in vivo to produce one ormore maribavir isomers.
 13. The method according to claim 1, whereinsaid compound comprises a pyranosyl analog of maribavir.
 14. The methodaccording to claim 7, wherein said composition comprises a pyranosylisomer of maribavir.
 15. A method for determining the therapeuticefficacy of the compound5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole,or an isomer of said compound in the blood plasma of a patientadministered said compound, comprising measuring the concentration of atherapeutically effective form of said compound in a blood plasma samplefrom said patient and comparing said measured concentration with theconcentration(s) of at least one of a lesser therapeutically effectiveform of said compound or an isomer or analog thereof in same patientsample.
 16. The method according to claim 15, wherein said measurementand comparison is performed on patient samples during and within 12hours of terminating treatment.
 17. The method according to claim 15,wherein said measurement(s) and comparison(s) determine the treatmentprotocol of said patient.
 18. The method according to claim 17, whereinsaid treatment protocol is the dosage amount of said compoundadministered to said patient, the dosage regimen for administration ofsaid compound to said patient, the discontinuation of administration ofsaid compound to said patient, or the initiation of other therapeuticintervention for said patient.
 19. A method of increasing thebioavailability of maribavir to a patient receiving maribavir therapycomprising administering to said patient an oral dose comprising about200 mg to 800 mg of maribavir under fasted conditions, whereby saidadministration results in an increase of the maximum plasmaconcentration and the extent of absorption of maribavir relative to theplasma concentration and the extent of absorption for the correspondingadministration of maribavir under fed conditions.
 20. A method ofinforming a patient receiving maribavir therapy that dosing of maribavirunder fasted conditions results in an increase of the maximum plasmaconcentration as compared to the administration of maribavir under fedconditions, comprising providing to said patient a container ofmaribavir doses, said container being associated with prescriptioninformation that advises the patient that administration of a maribavirdose under fasted conditions results in said increase.
 21. A method ofmore effectively and safely using maribavir therapy comprising providinginformation and guidance in maribavir product packaging and promotionalmaterials regarding the nature of in vivo isomerization of maribavir andrelated guidance on dosing and use of maribavir so as to mitigate anypotential undesired effects from said in vivo maribavir isomerization.22. A method of making one or more maribavir isomers comprising the stepof administering maribavir to a mammal, wherein said administrationresults in the in vivo isomerization of maribavir to one or moremaribavir isomers.
 23. The method according to claim 22, wherein thesaid mammal is human that has a herpes virus infection.
 24. Acomposition for the treatment or prophylaxis of herpes viral infectioncomprising the compound5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoleand at least one of an antacid which is effective for neutralizing acidthat catalyzes isomerization of maribavir, an antibiotic having activityagainst a microorganism that mediates isomerization of maribavir and anantagonist that inhibits metabolism that induces isomerization ofmaribavir, said isomerization producing a decrease in the therapeuticefficacy of said compound.